Cerebral accumulation of Amyloid beta (Abeta) peptides is an early event in establishing of Alzheimer's disease (AD) pathology. Based on the epidemiological evidence pointing to a link between cholesterol metabolism and AD and the numerous laboratory studies implicating cholesterol in the process of Abeta production and accumulation, it is now believed that cholesterol-lowering therapies will be of value as disease modifying agents. Several epidemiological studies revealed that statin use for the treatment of coronary arterial disease is associated with a decreased prevalence or a decreased risk of developing AD. The major objectives of this proposal are: to test the ability of different statins to delay the onset or retard the progression of brain Abeta deposition in the PSAPP transgenic mouse model of Alzheimer's amyloidosis, and to investigate the mechanisms by which statin treatment modulates brain Abeta accumulation. Our goal is to examine how the lipid-lowering as well as the anti-inflammatory/immunomodulatory activities of statins contribute to their effect on brain Abeta accumulation. To this end we will employ in vivo experimental paradigms using the PSAPP transgenic mouse model of Alzheimer's amyloidosis, as well as in vitro experimental paradigms using microglial and neuronal cultures. In the first specific aim we will compare the relative efficacy with which statins with different BBB permeability attenuate early as well as advanced Abeta deposition. We will then examine how statin treatments modulate APP processing and ApoE expression in brain (specific aim 2). Finally, we will evaluate the effects of statins on the inflammatory response in brain in the context of different paradigms of microglial activation and we will test their ability to prevent or attenuate Abeta-induced microglial neurotoxicity (specific aim 3). [unreadable] [unreadable]